title: Plasma concentrations and pharmacokinetics of dimethylsulfoxide and its metabolites in patients undergoing peripheral-blood stem-cell transplants.
abstract: OBJECTIVE
  Dimethylsulfoxide (DMSO) is used to cryopreserve hematopoietic stem cells and is obligatorily infused into patients who receive stem-cell transplants. This study characterized the plasma concentrations and pharmacokinetics of DMSO and its metabolites in patients who underwent peripheral-blood stem-cell transplants.
  
  
  METHODS
  Plasma concentrations of DMSO, dimethylsulfone (DMSO2), and dimethylsulfide (DMSH2) were assessed in 10 patients who underwent autologous transplants with stem cells, cryopreserved in 10% DMSO (vol/vol). Blood was sampled at multiple times after the stem-cell infusion. Urine was pooled during the 24 hours postinfusion. DMSO, DMSO2, and DMSH2 were assayed simultaneously by gas chromatography. A one-compartment model with saturable elimination proved most suitable for fitting plasma DMSO concentration-versus-time data.
  
  
  RESULTS
  Stem-cell volumes infused ranged between 180 and 585 mL (254 to 824 mmol DMSO). Infusions lasted between 20 and 120 minutes. Peak plasma DMSO concentrations were 19.1 +/- 6.3 mmol/L (mean +/- SD). Pharmacokinetic parameters for volume of the central compartment (Vc), maximum velocity (Vmax), and Michaels-Menten constant (Km) were 37.3 +/- 17 L, 0.99 +/- 0.57 mmol/L/h, and 5.2 +/- 5.0 mmol/L, respectively. Plasma DMSO2 concentrations increased during the first 24 hours, plateaued at 4.4 +/- 1.2 mmol/L, and remained there until 48 hours (the last sample). DMSH2 concentrations were at steady-state by 5 minutes and remained between 3 and 5 mmol/L for 48 hours. Urinary excretion of DMSO and DMSO2 accounted for 44% +/- 4% and 4% +/- 1%, respectively, of the administered DMSO dose. Renal clearance of DMSO was 14.1 +/- 3.4 mL/min.
  
  
  CONCLUSIONS
  These data (1) document plasma concentrations of DMSO and metabolites in patients following peripheral-blood stem-cell transplants; (2) allow consideration of potential effects of these concentrations on stem-cell engraftment and drug-drug interactions; and (3) can facilitate a concentration-guided phase I trial of DMSO.
authors.affiliation: Division of Developmental Therapeutics, University of Maryland Cancer Center, Baltimore 21201, USA. megorin@umaryland.edu
authors.forename: M J
authors.initials: MJ
authors.lastname: Egorin
authors.forename: D M
authors.initials: DM
authors.lastname: Rosen
authors.forename: R
authors.initials: R
authors.lastname: Sridhara
authors.forename: L
authors.initials: L
authors.lastname: Sensenbrenner
authors.forename: M
authors.initials: M
authors.lastname: Cottler-Fox
mesh_terms: D002849:Chromatography, Gas; D003451:Cryoprotective Agents / Q000493:pharmacokinetics*; D004121:Dimethyl Sulfoxide / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D014021:Tissue Preservation
chemical_list: D003451:Cryoprotective Agents; D004121:Dimethyl Sulfoxide